NO123805B - - Google Patents

Description

Analogy process for the preparation of new pharmacologically active derivatives of 1-sulfanyl-2-imino-imidazolidines.

The present invention relates to an analogous process for the production of new, pharmacologically active derivatives of 1-sulfanyl-2-imino-imidazolidines.

Compounds of the general formula I,

where R| means an alkyl or alkenyl group with at most 5 carbon atoms or a cycloalkyl or cycloalkenyl group with at most 7 carbon atoms and

R2 the methyl or ethyl group,

and their addition salts with inorganic and organic acids are not known to date.

As it was now found, these compounds possess valuable pharmacological properties, especially 1-sulfanily-2-imino-3-butyl-b-ethyl-, 1- sulfanily 1 -2-imino-3-M:er t. bu ty 1 -4 - methy 1-

and 1-sulfanilyl-2-imino-3-ter t.butyl-b-me phyl-imidazolide ine t exhibit hypoglycemic action upon peroral or parenteral administration, which characterizes them as suitable

for the treatment of diabetes. The hypoglycaemic effect is demonstrated by standard experiments on warm-blooded animals, e.g. on

rabbits and rats.

In the compounds of the general formula I, R^ can be

lower alkyl groups e.g. be methyl-, ethyl-, pfopyl-, isopropyl-, butyl-, sec.butyl-, tert.butyl-, isobutyl-,

the pentyl, isopentyl, 2,2-dimethyl-propyl, 1-methyl-butyl, 1-ethyl-propyl, 1,2-dimethyl-propyl group and as an alkenyl group e.g. the allyl, 1-, 2- or 3-buten-1-yl, 2-methyl-propenyl, metallyl or 3- or 4-penten-1-yl group. Furthermore, R-^ can e.g. be: as ey chloalkyl lgr uppe , cyclopropyl-, cyclo-propylmethyl-, 2-cyclopropylethyl-, 3-cyclopropyl-propyl-, cyclo-butyl-, cyclobutylmethyl-, 2-cyclobutyl-ethyl-,•3-cyclobutyl-propyl- , cyclopentyl-, 1-methyl-cyclopentyl-, 2-methyl-cyclopentyl-, 3-methyl-cyclopentyl-, 1-ethyl-cyclopentyl-, 2-ethyl-cyclopentyl-,

3-ethyl-cyclopentyl-, cyclopentylmethyl-, 2-methyl-cyclopentylmethyl-, 3-methyl-cyclopentylmethyl-, cyclohexyl-, 1-methyl-cyclohexyl-, 2- etc. tyL-cyclohexyl-, 3-methyl-cyclohexyl-, 4- methyl-1-cyclohexyl-, cyclohexyl-methyl or cycloheptyl--the group- and-- c-tjhi" "cyk l.onIkenylgr.uppe -2-cyclo-lopenlen- 1-yl-, -2-methyl-2-cyclopenten-l-yl-, 3-methyl-2-cyclopenten-l-yl-, 2-ethyl-2-cyclopenten-l-yl-, 3-ethyl-2 -cyclopenten-1-yl-, 3-cyclopenten-1-yl-, 2-methyl-3-cyclopenten-1-yl-, 3-methyl-3-cyclopentone-L-y1-, 2-ethyl-3-cyclopentene -l-yl-, 3-ethyl-3-cyclopenten- 1-y 1- , 2-cyclohexen-l-yl-, 1-rne ty 1-2-cyclo-hexen-l-yl-, 2 -methyl L-2-cyclohexen-1-yl-, 3-methyl-2-cyclo-hexene-1-yl, 4-methyl-2-cyclohexen-1-yl-, 3-cyclohexen- 1-yl-, 1- methyl-3-cyclohexen-1-yl-, 2-methyl-3-cyclohexen-1-yl-, 3- methyl-3-cyclohexen-1-yl-, 4-methyl-3- cyclohexen-1-yl-,

2- or 3-cyclopenten-1-ylmethyl-, 2-, 3- or 4-cyclohexen-1-ylmethyl-, 2-cyclohepten-1-yl-, 3-cyclohepten-1-yl- or 4 - cyclohept.en-L-y Iq.ruppen ..

According to a first method according to the invention, a compound of the general formula I is prepared, whereby mari reacts a. connection with the general formula II,

where R-^ and R ? got it. under the meaning given in formula I, R^ means hydrogen, the methyl or allyl group or, an arylmethyl, diarylmethyl or a triarylmethyl group and X a residue transferable by hydrolysis or reduction to the free amino group, or if R2 is hydrogen, also the free amino group ,

with a reactive cyanic acid derivative and cyclizes, if necessary, hydrolyzes the reaction product for conversion of

the group X to the free amino group or reduces and optionally transfers the compound obtained with an inorganic or organic acid to an addition salt.

R« is as arylmethyl, diarylmethyl or triarylmethyl group, e.g. the benzyl, benzhydryl or trityl group.

Halogen cyans, such as cyanochlorine or cyanobromine, or cyanic acid esters, especially cyanic acid phenyl ester, are suitable as reactive cyanic acid derivatives. The turnover finds preferably . place in the presence of a water-miscible or immiscible inert organic solvent. in the presence or absence of water.

Suitable inert organic solvents are e.g. hydrocarbons, such as benzene, toluene or xylene, lower alkanols, such as methanol or ethanol, ether-like liquids, such as ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons, such as methylene chloride, lower ketones, such as acetone or methyl ethyl ketone, carboxylic acid esters, such as ethyl acetate, - carboxyl -acid nitriles, such as acetonitrile, or sulfones, such as tetrahydro-thiophene-1,1-dloxide. The turnover can be carried out in the presence or absence of an acid-binding agent. Inorganic bases or salts are suitable as acid-binding agents, e.g. alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates or alkali metal phosphates, such as the corresponding sodium or potassium compounds. Furthermore, calcium carbonates as well as calcium phosphate and magnesium carbonate can also be used.

The subsequent conversion of the group X in the reaction product to the free amino group, which transfers this to a compound of the general formula I, is carried out, depending on the type of the group X, by hydrolysis, reduction or reductive cleavage.

Upon hydrolysis to the free amino group transferable residues X

is e.g. acylaminoreste.r , such as e.g. the acetamido group.

Furthermore, such residues are lower: alkoxycarbonylamino residues, such as e.g. the ethoxycarbonylamino group, aryloxycarbonylamino residues,

as phenoxykarhonyiam.inor-est.én', or a'rylmc.tql<sy.kar.bonylamino-r e-s te r, -as ^enzylok!3y^a''rbony'l;aininb.T.est'!; n, or rest-,of

."corresponding t-io'-kårbo'n acid derivatives..- Further <:>examples" are.

. substituted methylene amino esters, such as e.g. ' bon.zylidenam.ino-..' •or p-dLmotylamLno:-b"cn'zylidenåmlnbgruppcn.' The hydrolysis to release the amino group can take place in an acidic medium, e.g. in methanolic hydrochloric acid, -or in dilute aqueous hydrochloric acid or sulfuric acid, c Ltor,. if X-be ty r: an alkpcsyca rbonyiami.no-residue, can' also be Toretas under mil do" alk a IL shoe conditions, e.g.' using l-n oller 2-ji ' na t rohlut i '.*_'■•

An example, on on by -reduction L.il the amino group transfers Ltr. l. X is ni trog r: up pen and example of' such. remains '.of wood

reductive *.p;i.L l.n i ng forer to the amino group, is phenylazo-elLcr p-diinel.yiamino-phenyL-azogriippcr. The reduction of these res Le r can gencreLt find stood catalytic, f . ek'i.. -by the help of hydrogen in the presence of Raney-nikkoJ, palladium- or pla t.in-ku L L, in et. inert solvent, '..if f.ek:.: e.LanoL. Alongside these, other common reduction methods also come into consideration, e.g. redoxon ;iv nitio-grjpper etc. Ler dyn reductive .cleavage of azogi.ijpper with the help of iron in acetic acid or hydrochloric acid.

As a starting point: substances with the general ■ formula II, such compounds are suitable, whose symbols are R^, R 2." ^3 °9 * .agree*. with the groups listed in connection with formula I and II respectively. - .Such starting materials are N-.('2-amino-ethyl.l)-benzenesulfonamides-, where.. benzene ring is substituted with the residue X in the para position, whose amino group with the residues R^ as well as R^. and-if,- ctylgr.uppe in 1- or 2t's tilling with-methyl- or Vethylgruppeh. 'A- group of such compounds

can e.g. produced, when. Mon. starts from 1-phenylsulphonyl-2-methyl- or 1-phenylsulfonyl-2-ethyl-aziridin. which is substituted with the residue X, and reacts the aziridine with a primary or secondary elec. amiri, as in eti old is. the residues R.^ and.R-j.

Representatives of the aforementioned aziridines are required in the literature. A-. Weissbé:rg€r,; idea'te'rocycli'c'"Cbm'ppunds with' Three- .arid.. Four-Membered" Rings,. Par.t-. One, ." John Jlfiley &

Sons Inc. London (1964)]. Further aziridines of this type are prepared analogously.

Following a second method according to the invention, compounds with the general formula I, where R ? takes b-s t .111 no , while condensing a compound with the general formula III"

where R:^ has the meaning under formula I ang in f-f a -meaning and X means the amino group or a residue, which by hydrolysis or reduction-, can be transferred to the amino group, with a compound of the general formula IV,

where R^ has the meaning indicated under formula I, or with an alkali metal or alkali metal derivative of such a compound and cyclizes. hydrolyzes, if necessary, the reaction product to convert the group X - into the free amino group or reduces and optionally transfers the obtained compound with an inorganic or organic acid to an addition salt.

Suitable alkali metal or alkaline earth metal derivatives with the general formula IV are sodium, potassium, lithium and calcium derivatives respectively.<:> The condensation is preferably carried out in an ether-like liquid, such as "e.g. in ether, dioxane, ariisol or ethylene glycol dimethyl ether.

The group X has the same meaning as in the first method.

Its conversion to the free amino group, which transfers the reaction product -to a compound, with it. general formula I, may take place. as explained in the description,

for his procedure.

Suitable starting substances with the general formula III are such compounds, whose symbols X and correspond to the groups listed in connection with. formula II. One. the production possibility for such compounds has already been explained in connection with the first method.

After one. third method according to the invention compounds of the general formula I are prepared, by reducing a compound of the general formula V,

where FU has the meaning given under fqrmel I, R^' means an alkenyl group with 3-5 carbon atoms or a cycloalkenyl group with 5-7 carbon atoms and X the amino group or a residue, which by hydrolysis or reduction can be transferred to the free amino group,

and optionally transfers an obtained compound with an inorganic or organic acid to an addition salt.

The reduction is preferably carried out with hydrogen in the presence of a catalyst in a solvent. Suitable catalysts are e.g. precious metal catalysts, such as palladium, which e.g. used on coal and further Raney nickel. As solvents, e.g. alkanols, such as methanol or ethanol, further dioxane are used. It is advantageous to carry out the reduction at normal pressure and room temperature.

The group X has the same meaning as in the method understood. Its conversion to the free amino group therein, which transfers the reaction product to a compound of the general formula I, can take place as explained in the description of its method.

Starting substances with the general formula V can e.g. is prepared analogously to the first method, when starting from a 1-phenylsulfonyl-2-methyl or 1-phenylsulfonyl-2-ethylaziridine, which in the benzene ring is substituted with the residue X and reacting this aziridine with an alkenyl or cyclo-alkenyl-amine to a corresponding in the benzene ring with the residue X substituted N-(1-methyl-2-alkenylamino-ethyl)-, N-(1-ethyl-2-alkenyiamino-ethyl)-, N-(2-me ethyl-2-cycloalkenyl-amino-ethyl)-respectively N-(2-ethyl-2-cycloalkenylamino-ethyl)-benzenesulfonamide and condenses this with cyanogen bromide and "cyclizes".

Following a fourth method according to the invention, compounds are obtained with the general formula I, where one reacts the reactive functional derivative of a sulfonic acid against the general formula VI,

where X' means a residue, which by hydrolysis, reduction or reductive cleavage can be transferred to file one

amino group,.-

with a compound of the general formula Will,

where R , oq R,^ has' the under f brrnél ■ 1. ang it te tie tydning, hydrolyseror. reaction product for: conversion of the group X to the free amino group or reduction and transfer", if desired, don obtained compound with an inorganic or organic acid to. ot addition salt t. As reaction.ions d<y> suitable functional derivative of a sulfonic acid with the general formula VI is, for example, a halide, especially a chloride, or also an anhydride with the general formula Via,

where X' has the meaning given under formula VI.

The turnover preferably takes place in the presence of water

■miscible or immiscible inert organic solvent in the presence or absence of water. Suitable inert organic solvents ex e.g. hydrocarbons such as benzene, toluene or xylene, ether-like liquids such as ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride and lower ketones such as acetone or methyl ethyl ketone. It is advantageous to add an acid-binding agent to the reaction mixture. Suitable as such are, for example, inorganic bases or salts, which are listed in connection with the first method. Further lets. also organic bases, such as e.g. pyridine,

trimethyl- or triephylamln, N',N-diisopropyl-e phylarnine or collidine, can be used, which can also be added in excess. are used as solvents.

The residue X' has as residue, as in hydrolysis or reduction

can be transferred to the free amino group, the same meaning as the residue X in the understood method. Convert 1 son of the residue X' to the free amino group,. which transfers the reaction product to a compound of the general formula I, can also be carried out as explained for the residue X in the description of the first method.

As starting materials for the method, e.g. compounds of the general formula VII- are used, whose symbols R^ and R^ correspond to the groups enumerated in connection with form:l.-.I_......

A group of starting materials with the general formula VII are 2-amino-4-methyl as well as 2-amino-4-ethyl-2-imidazolyls, which are substituted in the 1-position with the remainder R-^. To the aforementioned 1-R-^-2-amino-4-methyl-2-imidazolines when one e.g.

as. following! One starts from 2-chloro-propionyl chloride and reacts this chloride with primary amines of the formula r^N-R-^ to N-R^-2-chloro-propionamides; these amides give with benzylamine N-R^-(2-benzylamino)-propionamides, which with lithium aluminum-1-2

hydride is reduced to N -R-^-N -benzyl-1,2-propanediamines;

the reduction products can be debenzylated with palladium charcoal and hydrogen to the corresponding N-R-^-1,2-propanediamines, which condense with cyanogen bromide during ring closure. Homologous 1-R,-2-amino-4-ethyl-2- imidazolines can be prepared analogously

by starting from 2-chloro-butyphyll chloride via the intermediate products N^R,-2-chloro-butyramides, 'N-R,-2-bénzylamino-butyramides, N 1 -R,-N 2-benzyl-1,2-butanediamines and - N 1 -R^-1,2-butanediamines..

A further group of starting substances with the general formula VII are 2-amino-b-methyl as well as 2-amino-5-ethyl-2-imidazolines, which are substituted in the 1-position with the residue R 1 .

The aforementioned 1-R^-2-amino-5-methyl-2-imidazolines can e.g.

is prepared starting from 2-chloro-propionyl chloride. One sells e.g. this carboxylic acid chloride with benzylamine to the N-benzyl-2-chloro-propionamide, which with primary amines of the formula f^N-R^ gives N-benzyl-2-(R^-amino)-propionamides; these amides are reduced with lithium aluminum hydride to N 1 -benzyl-N 2-R,-1,2-propanediamines, which are debenzylated with hydrogen in the presence of a catalyst to N 2-R-^-1,2-propanediamines and finally the obtained are condensed diamine with cyanogen bromide and cyclize.

The compounds of the general formula I obtained according to the process according to the invention are then transferred, if desired, to their salts with inorganic as well as organic acids. The production of these salts can be found e.g. place in the reaction of compounds of the general formula I

with the equivalent amount of an acid in a suitable aqueous-organic or organic solvent, such as e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.

For use as pharmaceuticals, instead of the free compounds of the general formula I, their pharmaceutically acceptable salts with acids can be used. Suitable addition salts are e.g. salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

The new active substances are preferably administered orally.

The daily doses range between 100 and 500 mg for adult patients of normal weight. Suitable dosage unit forms, such as dragées, tablets, preferably contain 50,500 mg of an active substance according to the invention and namely 20 to 80% of a compound of the general formula I.

The following examples explain their production

new compounds with the general formula I. The temperatures are given in degrees Celsius.

EXAMPLE 1

a) Dissolve 32.7 g of N<1->(1-methyl-2-tert.butylamino-ethyl)-N<4->acetyl-sulfanilamide in 100 ml of 2-n caustic soda and add

while cooling at 20 - 30° IO.6 g of cyanogen bromide. The crude product precipitates as crystalline. It is filtered off after 30 minutes and recrystallized from N,N-dimethylformamide. The resulting 4'-(2-imino-3-tert.butyl-5-methyl-imidazolidin-1-ylsulfonyl)-acetanilide melts at 243-244°.

b) to 125 g of 50% sulfuric acid heated at 40°, 35.2 g of the acetanilide obtained according to a) is added with stirring. Mon

heat the mixture for 2 hours at 50° and pour the solution

then, while stirring, add 750 ml of water. The crude product precipitates as sulphate. The pH of the reaction mixture is set to 6.3 with 10-n caustic soda. The mixture dissolves except for small impurities; it is stirred with 2 g of activated carbon for 15 minutes and filtered over Hyflo (purified diatomaceous earth). The filtrate is made alkaline with 10-n caustic soda. The crude product precipitates out. It is filtered off, washed with water, dried at 90° and recrystallized from acetic acid ethyl ester. The 1-sulfanyl-2-imino-3-tert.butyl-5-methyl-imidazolidine obtained melts at 145 - 146°.

c) The starting compound mentioned under a) is obtained as follows: A solution of 23.3 g of N-acetyl-sulfanyl chloride

in 70 ml of acetone is added dropwise with stirring at -10° to 0° to 5.6 g of 2-methylaziridine in 30 ml of 4-n sodium hydroxide solution. You row. the reaction mixture at 0° for a further 2 hours and then pour it into 400 ml of ice water. The resulting suspension is filtered from the precipitate, the crude 4-(2-methyl-aziridin-1-ylsulphyl)-acetanilide, washed with water and further processed so that it easily polymerizes.

d) The acetanilide obtained according to c) is dissolved in the cold in 100 ml dioxane and 15 ml water and dripped to the solution

100 ml tert.butylamine. The reaction mixture is then boiled for one hour under reflux and the excess tert-butylamine as well as the dioxane are distilled off. The crystalline residue from acetic acid ethyl ester is recrystallized, after which the pure N 1 -(.1-methyl-2-tert.butylamino-ethyl)-N 4-acetyl-sulfanilamide melts at 93 - 95°.

EXAMPLE 2

a) Analogous example 1 a) is obtained by starting from 28.5 g. 10.6 g of cyanobromo 41 -(2-imino-3,5-dimethyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 258 - 260°, of which 31.0 g analogous to example 1 b) is hydrolysed with 125 g of 50% sulfuric acid to the end product 1-sulfanyl-2-imino-3,5-dimethyl-imidazolidine with m.p. 196 - 197°. b) The starting substance of a) is obtained analogously to example 1 c) from 2b.4 g of A'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide

(sml- example 1 c) and 200 ml of 33% methylamine in ethanol.

E X E M P E L. 3

a) Analogous example la) is obtained by starting from 29.9 g of N"*"-(1-methyl-2-ethylamino-ethyl)-N4-acety 1-sulfan in lam id (- crude product) with 10.6 g bromcyan A 1 ~-(2-imino-3-ethyl-b-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 229 - 230°,

of which t 32, A q analogous t example 1 b ). hydrolyzed with 12b g of sulfuric acid. the final product 1-sulfanyl-2-i-mino-3-ethyl-b-methyl-imidazolidine.

b) The starting substance of a) is obtained analogously to example 1 c) from. 2b,4 g 4 - ( 2-methyl 1-azir idirv-1-yl sulf ony 1 )-acetan yl i d

(cf. example 1 c) and 2bO ml of 20% ethylamine in benzene.

EXAMPLE - 4

a) Analogous example.1 a) is obtained by starting from 31.3 g of N - (1-methyl-2-propylamino-ethyl).

m.p. 162 - 163° with 10.0 g of cyanogen bromide. 4'-f 2-imino-3-propyl-b-methyl-imidazolidin-1-ylsulfonyl)-a-cet-anilide with m.p. 2b4 - 2bb°, of which 33.8 g analogous example. 1 b) is hydrolyzed with 12b g b0% sulfuric acid to the final product 1-sull anil yl-2-imino-3-propyl-b-methyl-imidazolidine with m.p. 146 - 148°.

b) The starting substance of a) is obtained analogously to example 1 c) from 2b, 4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide

(cf. example 1 c) and 100 ml of propylamine.

EXAMPLE 5

a) Analogous example la) is obtained by starting from 32.7 g of N 1 -(1-methyl-2-butylamino-ethyl)-N 4-acetyl-sulfanilamide with

m.p. 166 - 167° with 10.6 g of cyanobromo 4'-(2-imino-3-butyl-b-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 243 - 244°, of which 3b.2 g of analogous example lb) is hydrolyzed with 12b g of b0/é'ig sulfuric acid to the final product. I-sulfanyl-2-imino-3-butyl-b-methyl-imidazolidine with m.p. 12b - 126°.

b) The starting substance of a) is obtained analogously to example 1 c) from 2b, 4 g of A'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide

(cf. example 1 c) and 100 ml of butylamine.

EXAMPLE 6

a) Analogous to example 1 a) one obtains by going out ira 32.7 g of N^-(I-methyl-2-sec.butylamino-ethyl)-N<4->acetyl-sulfanilamide

with m.p. 118 - 120° with 10.6 g of cyanobromide A '-(2-imino-3-sec.buty1-b-methyl - irnidazo 1 id in-1-yl sulfony 1)-acetani 1 id:- with . m.p. 242 - 244°,. of which 3b.2 g analogous to example 1 b) is hydrolysed with 12b g b0% sulfuric acid to the final product 1-sulfanylyl-2-imino-3-sec.bu fy1-b-methyl-imidazolidin with m.p. 194 - 19b°. I.i) The starting substance of a) is obtained analogously to example 1 c) from 2b, 4 g of 41 -(2-methyl-azirid in-1-ylsulfonyl)-acetani 1 id (cf. example 1 c) and 100 rnl : sec1, bu ty larnin .

EXAMPLE. 7

a) Analogous to example 1 a)" is obtained by starting from 34.1 g of N 2 -(1-methyl-2-pentylamino-e phyl)-N 4 -ace ty1-su 1 phenylamide

(crude product) with 10.6 g of cyanobromo 4 1 -(2-imino-3-pentyl-b-methyl-imidazolidin-1-yl sulphonyl)-acephanilide with m.p. 228 - 229°,

of which 36.4' g analogously, example 1 b) is hydrolysed with 12b g of 20% sulfuric acid to the end product 1-sulfanyl-2-imino-3-penty1-b-methyl-imidazolidin with m.p. 127 - 128°.

b) The starting substance of a) is obtained from anionic example 1 c) from 2b,4' g 4' - (2-methyl-azirid in-1-yl sulfonyl)-acetanyl id

(cf. example 1 c) and 100 ml of pentylamine.

EXAMPLE 8

a) analogous to example 1 a) is obtained by starting from 3b, 1 g of N"<*>"-(.1-methyl-2-cyclohexylamino-ethyl)-N 4-acetyl-sulfanilamide

(crude product) with 10.6 g of cyanobromo 41 -(2-imino-3-cyclohexyl-b-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 23b - 237°, of which 37.6 g analogous to example 1 b) is hydrolyzed with 12b g b0% sulfuric acid to the end product 1-sulfanyl-2-imino-3-cyclohexyl-b-methyl-imidazolidine mecf m.p. 217 - 218°.

b) The starting substance of a) is obtained analogously to example 1 c) from 25.4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide

(cf. example 1 c) and 100 ml of cyclohexylamine.

EXAMPLE 9

a) Analogous example 1 a) is obtained by starting from 34.9 g of N^-[1-methyl-2-(3-cyclohexen-1-ylamino)-ethyl]-N<4->acetyl-sulfanilamide with m.p. 139 - 141° with 10.6 g of cyanobromo 4'-[2-imino-3-(3-cyclohexen-1-yl)-5-methyl-imidazolidin-1-ylsulfonyl]-acetanilide with m.p. 270 - 271°, off. which 37.4 g analogous to example 1 c) is hydrolysed with 125 g of 50% sulfuric acid to the final product 1-sulfanyl-2-imino-3-(3-cyclohexen-1-yl)-5-methyl-imidazolidine with m.p. 208 - 209°. b) The starting substance of a) is obtained analogously to example 1 c) from 25.4 g of 41-(2-methyl-aziridin-1-ylsulionyl)-acetanyl id

(cf. example 1 c) and 100 ml of (3-cyclohexen-1-yl)-amine.

■c ) Furthermore, the 1-sulfanyl-2-imino-3-tert.butyl-4-methyl-imidazolidine is prepared analogously to example 1 a) with m.p. 178 -

180° (from isopropanol) and the 1-sulfanyl-2-imino-3-butyl-5-ethyl-imidazolidine with m.p. 161 - 163°.

EXAMPLE 10

a) Analogous example 1 a) is obtained by starting from 32.7 g of N 1 - i (1-methyl-2-tert.butylamino-ethyl)-N 4-acetyl-sulfanilamide

with m.p. 93 - 95° (from acetic acid ethyl ester) with 6.5 g of cyanogen chloride or with 11.9 g of phenylcyanate instead of cyanogen bromide 4'-(2-imino-3-tert.butyl-5-methyl-imidazolidin-1-ylsulfonyl)- acetanilide with m.p. 243 - 244° (from N,N-dimethylformamide), of which 35.2 g according to example 1 b) is hydrolyzed to the final product 1-sulfanylyl-2-imino-3-tert.butyl1-5-methyl-imidazolidine with m.p. 145 - 146° (from acetic acid ethyl ester).

b) The starting substance of a) is obtained according to example 1 c - d) from 24.0 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide and 100

ml tert.butylamine.

EXAMPLE II

A solution of 14.6 g of tert.butylamine in 100 ml of abs. ether is added with stirring at -10° to -5° over the course of 30 minutes to a solution of 10.6 g of cyanogen bromide in 50 ml of abs. ether. The reaction mixture is stirred for a further 30 minutes and the precipitated tert-butylamine hydrobromide is filtered off. The filtrate, in which the obtained tert-butylcyanamide is dissolved, is added and further cooled with a suspension of 2.8

g sodium hydride in 40 ml abs. Otter. The suspension is stirred, which is further cooled at the same temperature, for another 30 minutes, and then 25.4 g of 4'-(2-tyl-aziridin-1-ylsulfonyl)-acetani 1 are added to the suspended sodium derivative of tert-butylcyanamide formed. id. The mixture is heated at room temperature and stirred for 15 hours at this temperature. The reaction mixture is then slowly added with 2-n hydrochloric acid and the two phases formed are separated. The acidic, aqueous phase is washed twice with ether, cleaned with activated charcoal, filtered and made alkaline at 0° with concentrated caustic soda. The precipitated 4'-(2-imino-3-tert-butyl-5-methyl-imidazolidin-1-ylsulfonyl)-acetanilide is filtered off and recrystallized from chloroform ethanol, after which it melts at 238 - 240°.

The acetanilide obtained is hydrolyzed according to example 1 b)

to the l-sulfanyl-2-imino-3-tert.butyl-5-methyl-imidazolidine with m.p. 14 5 - 146°.

EXAMPLE 12

Analogous to example 11, one obtains:

a) from 14.6 g of butylamine in 100 ml of ether with 10.6 g of bromcyan butylcyanamide, which is added with 2.8 g of sodium hydride in 40

ml of ether to the sodium derivative; this gives 25.4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide 4'-(2-imino-3-butyl-5-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. . 243 - 244, which is analogous to example 1 b) is hydrolysed to 1-sulfanyl-2-imino-3-butyl-5-methyl-imidazolidine with m.p. 125 - 126°;

b) from 17.4 g of pentylamine in 100 ml of ether with 10.6 g of the bromocyan pentylcyanamide, which is treated with 2.8 g of sodium hydride

in 40 ml of ether to the sodium derivative; this gives 25.4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide 4'-(2-imino-3-pentyl-5-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 228 - 229°, which analogously to example 1 b) is hydrolyzed to the 1-sulfanyl-2-imino-3-pentyl-5-methyl-imidazolidine with m.p.

127 - 128°;

c) from 19.6 g of 3-cyclohexen-1-ylamine in 100 ml of ether with 10.6

g of the cyanobromo(3-cyclohexen-1-yl)-cyanamide, which is transferred

with 2.8 g of sodium hydride in 40 ml of ether to the sodium derivative; this gives 25.4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide 4'-[2-imino-3-(3-cyclohexen-1-yl)-5-methyl-imidazolidin-1 -ylsulfonyl]-acetanilide with m.p. 270 - 271°, which analogously to example 1 b) is hydrolysed to the 1-sulfanilyl-2-imino-3-(3-cyclohexen-1-yl)-5-methyl-imidazolidine with m.p. 208 - 209°; d) v. from 19.8 g cyclohexylamine in 100 ml ether with 10.6 g bromcyan cyclohexyl cyanamide, which with. 2.8 g of sodium hydride in 40 ml of ether are transferred to the sodium derivative; this gives 25.4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide 4'-(2-imino-3-cyclohexyl-5-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 235 - 237°, which is analogous to example 1 b) is hydrolyzed to 1-sulfanyl-2-imino-3-cyclohexy1-5-methyl-imidazolidine with m.p. 217 - 218°. e) from 14.6 g of sec.butylamine in 100 ml of ether with 10.6 g of bromcyan butylcyanamide, which is treated with 2.8 g of sodium hydride in

40 ml of ether to the sodium derivative; this gives 25.4 g of 4'-(2-methyl-aziridin-1-ylsulfonyl)-acetanilide 4'-(2-imino-3-sec.butyl1-5-methyl-imidazolidin-1-ylsulfonyl)- acetanilide with m.p. 242 - 244°, which analogously to example 1 b) is hydrolyzed to the 1-sulfanyl-2-imino-3-sec.butyl-5-methyl-imidazolidine with m.p. 194 - 195°, and

f) from 14.6 g of butylamine in 100 ml of ether with 10.6 g of bromine cyanobutylcyanamidote, which with 2.8 g of sodium hydride in 40 ml of ether is transferred to the sodium derivative; this gives 26.8 g of 4'-(2-ethyl-aziri d in-1-y1 sul f ony1 ) - acetan il id 4 ' - ( 2 - imino-3 - bu ty 1 - b-e ty 1 - imidazolidin-1-yl sulphonyl)-acetanyl idet (crude product) with m.p.

107 - 111°, what an analogous example. 1 b) is hydrolyzed until . 1-

sul i a ni ly 1-2 - Imino-3-bu tyl - b-e tyl - imida zolidine with srnp.

161 - 163°;

EXAMPLE- 13

33.b g of i-sulfa-nylyl-2-imino-3-(3-cyclohexen-1-yl)-b-methyl-imidazolidine is hydrogenated in 3b0 rnl of dioxane with b .0 g of b%'ig palladium ku.il by being 1 see tempora tur and normal pressure. After the hydrogen uptake ice has ended, the catalyst is filtered off

and the filtrate is evaporated. One obtains 1-sulfanyl-2-imino-3-cyclo-hex sy .1-b-methy 1 - imidazol id ine t with m.p. 217 - ,2.18° (from

methanol).

EXAMPLE 14

a) 31.0 g of crude N^-tert.buphyl-1,2-propanediamine dihydrobromide is added to a solution of 13.2 g of cyanogen bromide in 220 ml of ether.

A solution of 11.4 g of sodium carbonate I in 88 ml of water is added to this mixture in portions over the course of 2 minutes. The obtained suspension is stirred for 1 hour at room temperature and allowed to stand for 2 days. The aqueous layer is separated, which contains 1-tert. bu ty 1-2 - arnino-4 - me ty 1 - 2- imidazol ine t, from the ether solution and diluting the aqueous phase with water,

to dissolve the precipitated sodium bromide. One adds the aqueous solution with one of 23.8 g of N-acetyl-sulfanyl chloride in 220 ml of acetone and. further with a solution of 8.8 g of sodium hydroxide in 44 ml of water.' The mixture is then refluxed for 30 minutes, cooled, the precipitated crude product is filtered off and recrystallized for 11 hours from chloroform-ethanol.

One obtains 4'-(2-imino-3-tert.butyl-b-methyl-imidazolidin-1-ylsulfonyl)-acetanilide with m.p. 238 - 240°.

b) 35.2 g of the acetanilide obtained according to a) is dissolved in 180

ml 8-n ethanolic hydrochloric acid and this solution is left to rest

2 days at room temperature. The reaction mixture is evaporated and the residue dissolved in water. The solution is filtered and made alkaline with caustic soda. The precipitated crystals are filtered off, washed with water and recrystallized from acetone-me ta no 1, which refers to 1-sulfanily 1-2-imino-3-tert. hu ethyl-, b-methyl-imidazolide melts at 14b - 146°.

The starting product of a) can be produced as follows:

c) 16.3b g N-tert. butyl-2-chloro-propionamide ■[ sml.. J-Am .Chern. Soc. 78, 6124 (19b6)] and 2bv0 g of benzylamine are heated for 3.b hours

at a bath temperature of IbO - 170°. From the reading, which is homogeneous at first, crystals precipitate out. The reaction mixture is cooled and 10 ml of 2-n caustic soda and chloroform are added. The organic phase is separated, washed with water, dried and evaporated. The residue is distilled. After a course of benzylamine, one obtains N-ter f . bu ty the 1 -2-benzyl arnino-propionamide with bp. 123 - 12b°/G.03 torr. The hydrochloride melts at lb8 - 162°.

d )v- File a suspension of 9.0 g 1 i t i urna 1 umini umhyd r id in 200 ml abs. tetrahydrofuran, a solution of 23.4 g of the amide obtained according to c) in 80 rnl abs is added dropwise over the course of 1b minutes. tetrahydrofuran. The suspension is then boiled for 38 hours under reflux. It first turns raspberry rqd and within 30 minutes gray again. The reaction mixture is cooled, the excess lithium aluminum hydride is destroyed while cooling with acetic acid ethyl ester, then with water and with methanol and the suspension is evaporated. The gray residue is extracted twice with boiling chloroform over the course of 30 minutes and filtered. The combined chloroform solutions are dried over sodium sulfate and vaporizes them. The remaining oil is distilled. N - tert.butyl-N 2 -benzyl-1,2-propanediamine distills<r> at 72-86°/0.00b.torr.

e) 22.0 g of the amine obtained according to d) in 440 ml of distilled ethanol is added to 34.0 g of 48% pure hydrogen bromide and 8.8 g of 5%

ig palladium charcoal and hydrated at room temperature and normal pressure. After 9b% of the calculated amount of hydrogen is occupied,

add a further 8.8 g of 5% palladium charcoal and hydrate further. After 17 hours, the reaction mixture has taken up 98% of the calculated amount of hydrogen. The catalyst is filtered off, washed with ethanol and the filtrate evaporated. The remainder, the N^"-tert. butyl-1,2-propanediamine-dihydro-bromide, is used as crude product.

EXAMPLE 15

a) Analogously to example 14 a-b), the following end product is obtained: From N-butyl-1,2-propanediamine and cyanobromide 1-butyl-2-amino-4-methyl-2-imidazolidine hydrobromide (crude product), which with N-acetyl-sulfanyl chloride gives 4'-(2-imino-3.-butyl 1-5-methyl-imidazoyl in-1-ylsulfonyl)-acetate in 1 ide with m.p. 243 -'244°, whose hydrolysis "gives the 1-sulfanylyl-2-imino-3-butyl 1-5-methyl 1-imidazolidine with m.p. 125 - 126°.

The starting product is obtained as follows:

b) One drips under good ice cooling in the lopot. of 30 minutes 12.7 g of 2-chlor-propiony 1 chlor id in 20 ni in chloroform fil on solution of 16.1 g of butylamine in 50 ml of chloroform. The solution obtained is allowed to stand for 15 minutes at room temperature, then washed several times with water and the organic phase is separated. One forks the organic phase over na f r iufnsu 1 f a t and evaporates it. The return is crude N-buphyl-2-chloro-propionamide. c) Analogous to example 14' c-e) the liine is obtained by passing ul from the crude amide of b) over the intermediate products N-butyl-2-benzyl-amino-propionamide with bp. 151 - 154°/0.005 torr and N^-bufy1-N^-benzyl-1,2-propanediamine with b.p. 98 - 104°/0.04 torr N-butyl-1,2-propanediamine.

EXAMPLE 16

a) Analogous to example 14 a-b), the following end product is obtained: From N-butyl-1,2-butanediamine (crude product) with cyanobromide the 1-butyl-2-amino-4-ethyl-2-imidazoline dihydrobromide (crude product), which with N-ethylsulphyl chloride gives 4'-(-2-imino-3-butyl-5-ethyl-imidazolidin-L-ylsulfonyl)-acetanilide (crude product)

with m.p. 107 - 111°, which is hydrolysed to 1-sulfanyl-2-imino-3-butyl-5-ethyl-imidazolidine with m.p. 161 - 163°.

Output compound 1 of a) is produced as follows:

b) Analogous to examples 15 b) and 14 c-e), one achieves by walking

starting from 2-chloro-butyryl chloride over the intermediates N-butyl-2-k Lor-butyramide (crude product), N-butyl-2-benzylamino-butyramide (crude product) and N^-butyl-N^-benzyl-l ,2-butanediamine (crude product)

N - but yl-1,2-bu tand iamine t.

EXAMPLE 17-

a) Dissolve 23.6 g (0.1 mol) 1-tert.butyl-2-amino-5-methyl-2-imidazoline hydrobromide in 100 ml of water and add 21.8 g (0.1 mol) N -acetyl-sulfanyl chloride .in 200 ml of acetone. Then, over the course of 10 minutes, a solution of 10.0 g of sodium hydroxide in 40 ml of water is added dropwise and the resulting suspension is boiled for 45 minutes under reflux. The reaction mixture is then cooled. The acetone is evaporated under vacuum. add water to the residue and take up the precipitated oil in methylene chloride. The methyl chloride solution ■ is treated over sodium sulfate and evaporated. The residue is crystallized from methanol. 4'-(2-imino-3-tert.butyl- 4-methyl-imidazolidin-1-yl)-acetanilide melts at 178 - 180°. b) The reaction product obtained according to a) is hydrolysed analogously to example 14 b) to 1-sulfanyl-2-imino-3-tert.butyl-4 -methyl-imidazolidine with mp 178 - 180° (from isopropanol).

The starting compound, 1-tert.butyl-2-imino-5-methyl-2-imidazolidine, can be prepared as follows: c) - 12.7 g of 2-chloro-propionyl chloride are dissolved in 50 ml of chloroform. The solution is dripped over the course of 45 minutes to one

dissolving 22 g of benzylamine in 70 ml of chloroform, stirring the reaction mixture for one hour at room temperature and then adding

water. Benzylamine opiates sog. The chloroform solution is separated and washed. against water. The aqueous phase is washed once with water and this aqueous phase is extracted with chloroform. The combined chloroform solutions are dried over sodium sulfate and evaporated. The residue is crystallized from methylene chloride-cyclohexane, after which the N-bonzyl-2-chloro-propionamide melts at 74 - 76°.

d) 19.75 q of that. according to c) the arnide obtained is dissolved in 20 g of tert butylamine and: the obtained solution is heated in

the autoclave 3.5 fimer at 150°. The reaction mixture is then diluted with ether and water. The organic phase is separated and extracted several times with 6-n hydrochloric acid. The combined phases are combined and made alkaline while cooling with concentrated caustic soda. The oil, which precipitates out, is extracted with ether, then the solution is dried over sodium sulfate and evaporated. The remaining N-benzyl-2-fert;-butylamino-propionamide distills under high vacuum, bp. 119 - 120°/0.01 torr..

e) Dissolve 23.4 g of the amide obtained according to d) in 50 ml abs. tetrahydrofuran. The solution is added dropwise over the course of 30 minutes while cooling to a suspension of 9 g lithium aluminum hydride in 170 ml abs. tetrahydrofuran and reflux the suspension for 39 hours. The reaction mixture is cooled, 9 ml of water, 18 ml of aqueous 15% sodium hydroxide solution and 27 ml of water are added dropwise. The formed precipitate is filtered off, the filtrate is evaporated under vacuum and the residue is distilled under high vacuum. The formed N 1 -benzyl-N 2 -tert.butyl-1,2-propanediamine boils at 74-80°/0.01 torr.

f). 22 g of the diamine obtained according to e). dissolve in 220 ml of ethanol. 34 g pure concentrate is added to the solution

hydrobromic acid and 5 g of 5/6'ig. palladium charcoal. The mixture is hydrated with hydrogen at atmospheric pressure and be 1 see temperature. In the course of the hydration, 3 g of palladium charcoal are added twice. After the hydrogen uptake has ended, the catalyst is filtered off and the filtrate is evaporated in a vacuum. The

obtained, crude oily N -tert.butyl-1,2-propanediamine-hydro-

bromide is added to 12/7 g of cyanogen bromide in 150 ml of ether. A solution of 11 g of sodium carbonate in 50 ml of water is added dropwise over the course of 15 minutes to the resulting suspension. The oil opiates during the formation of carbon dioxide. The mixture is stirred for 15 hours at room temperature. The aqueous phase,

which contains the crude l-tert.butyl-2-amino-5-methyl-2-

imidazoline, used ia).

Claims (1)

1. Analogy method for the preparation of new, pharmacologically active derivatives of l-sulfanylyl-2-imino-imidazolidines with the general formula I, where means an alkyl or alkenyl group with at most 5 carbon atoms or a cycloalkyl or cycloalkenyl group with at most 7 carbon atoms and R2 the methyl or ethyl group, and their addition salts with inorganic or organic acids, characterized in that one (a) reacts a compound with the general formula II, where Rj^ and R2 have the meaning given under formula I, R^ means hydrogen, the methyl or allyl group or an arylmethyl, diarylmethyl or a triarylmethyl group and X a residue transferable by hydrolysis or reduction to the free amino group, or if R^ is hydrogen, also the free amino group, with a reactive cyanic acid derivative and cyclizes, if necessary hydrolyzes the reaction product to convert the group X into the free amino group or reduces, and optionally transfers the compound obtained with an inorganic or organic acid to an addition salt or (b) one condenses a compound of the general formula III, where R2 has the meaning given in claim 1 under formula I and X means the amino group or a residue, as in hydrolysis. or reduction can be transferred to the amino group, with a compound of the general formula IV, where R has the meaning given in claim 1 under formula I, or with an alkali metal or alkaline earth metal derivative of such a compound and cyclizes, hydrolyzes, if any1; ^reaction product to"conversion of. the group X to the free amino group or reduces and optionally transfers the compound obtained with an inorganic or organic acid to an addition salt, or (c) one reduces a compound of the general formula V, where R2 has the meaning given in claim 1 in formula I, R^' means an alkenyl group with 3-5 carbon atoms or a cycloalkenyl group with 5-7 carbon atoms and X means the amino group or a residue, which by hydrolysis or reduction can be transferred to the free amino group, and possibly transferring a compound obtained with an inorganic or organic acid to an addition salt, or (d) one reacts a reactive functional derivative of a sulfonic acid with the general formula VI, where X' means a residue, which by hydrolysis, reduction or reductive cleavage can be transferred to an amino group, with a compound of the general formula VII, where R, and R2 have the meaning stated in claim 1 under formula I, hydrolyzes the reaction product to convert the group X to the free amino group or reduces and transfers, if desired, the obtained compound with an inorganic or organic acid to an addition salt.